The present invention relates to a process for the production of 2-amino-2-[2-(4-C2-20-alkyl-phenyl)ethyl]propane-1,3-diols, particularly 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol of formula 
hereinafter defined as Compound A.
2-Amino-2-[2-(4-C2-20-alkyl-phenyl)ethyl]propane-1,3-diols are disclosed in EP-A1-627,406 the relevant disclosure of which is incorporated herein by reference. On the basis of observed activity, e.g. as described in EP-A1-627,406, they have been found to be useful e.g. as immunosuppressants, e.g. in the prevention or treatment of acute allograft rejection or autoimmune diseases, or e.g. as described in WO 98/22100, in the prevention or treatment of xenograft rejection.
In accordance with the present invention, new processes for an improved production route of 2-amino-2-[2-(4-C2-20-alkyl-phenyl)ethyl]propane-1,3-diols, particularly Compound A, in free form or in salt form, have now been found. It is to be understood hereinafter that the process steps of the invention may lead to 2-amino-2-[2-(4-C2-20-alkyl-phenyl)ethyl]propane-1,3-diols in free form which may be converted into a salt form, or vice versa.
Accordingly, there is provided a process for preparing a 2-amino-2-[2-(4C2-20alkyl phenyl)ethyl]propane-1,3-diol, in free form or in salt form, which process comprises
g) reducing a compound of formula (20) 
wherein R is C2-20alkyl, each of R1 and R2, independently, is C1-4alkyl and R3 is a protecting group, followed by a treatment with (R4xe2x80x94CO)2O wherein R4 is C1-4alkyl, to obtain a compound of formula (21) 
wherein R, R3 and R4 are as defined above; and
i) treating the resulting compound of formula (21) with a basic compound to obtain a compound of formula (22) 
wherein R is as defined above; and
j) hydrogenating the resulting compound (22)
Any alkyl group mentioned herein may be a straight or branched chain alkyl group. Preferably C2-20alkyl is octyl, particularly straight chain.
Examples of protecting groups as R3 are e.g. disclosed in xe2x80x9cProtective Groups in Organic Synthesisxe2x80x9d, T. W. Greene, J. Wiley and Sons NY (1981), 219-287, e.g. acyl such as formyl, acetyl, benzoyl; alkoxycarbonyl e.g. t.-butyloxycarbonyl; allyloxycarbonyl; trityl; etc.
The reduction step g) may conveniently be performed using a reducing agent, e.g. NaBH4. The following treatment with an anhydride may be effected e.g. with acetic anhydride, preferably in the presence of a neutralizing agent, e.g. an aliphatic or organic amine, e.g. pyridine.
Suitable basic compounds for use in step i) include an alkali metal hydroxide, e.g. NaOH, KOH or LiOH. Step i) may preferably be carried out in a polar solvent, e.g. an alcohol such as methanol, at reflux. Step j) may be effected in accordance with known hydrogenation methods, e.g. in the presence of a hydrogenation catalyst, e.g. Pdxe2x80x94C.
As an alternative to above process, a 2-amino-2-[2-(4-C2-20alkylphenyl)ethyl]propane-1,3-diol in free form or in salt form may be prepared by
h) hydrogenating a compound of formula (21) as defined above to obtain a compound of formula (9) 
wherein R, R3 and R4 are as defined above; and
N) treating the resulting compound of formula (9) with a basic compound.
Steps h) and N) may be effected in accordance with methods known in the art, e.g. as disclosed above for steps j) and i), respectively, or in Examples 4 and 5 hereinafter.
According to a further embodiment of the invention, there is provided a process for preparing 2-amino-2-[2-(4-C2-20alkylphenyl)ethyl]propane-1,3-diol, in free form or in salt form, which process comprises
x) reducing a compound of formula (20) as defined above, followed by a treatment with (R4CO)2O to obtain a compound of formula (9) as defined above; and
N) treating the resulting compound of formula (9) with a basic compound.
In process step x) the reduction may comprise either a hydrogenation step, e.g. as disclosed above for step (j), followed by a reduction step, e.g. as disclosed above for step (g), or a reduction step as disclosed for step (g) comprising an intermediary hydrogenation step [e.g. as disclosed for step (j)] prior to the anhydride (R4 CO)2O treatment. Step (N) may be carried out as indicated above.
In a further or alternative embodiment, the invention provides a process for preparing 2-amino-2-[2-(4-C2-20alkylphenyl)ethyl]propane-1,3-diol, in free form or in salt form, which process comprises
f) hydrogenating a compound of formula (20) as defined above or a compound of formula (20xe2x80x2) 
wherein R1, R2 and R3 are as defined above, and Rxe2x80x2 is C1-19xe2x80x94COxe2x80x94 to obtain a compound of formula (8) 
wherein R and R1 to R3 are as defined above; and
K) reducing the resulting compound of formula (8) followed by a treatment with (R4CO)2O to obtain a compound of formula (9) as defined above; and
N) treating the resulting compound of formula (9) with a basic compound.
Process steps (f) and (K) may be performed as disclosed above for (j) and (g), respectively. Alternatively, the reduction step (K) may be carried out in the presence of Ca (BH4)2. The latter may be generated by reaction of NaBH4 with CaCl2.
Compound of formula (20xe2x80x2) may be prepared as disclosed in PCT/JP98/02998.
In a further or alternative embodiment, the invention further provides a process for preparing a 2-amino-2-[2-(4-C2-20alkylphenyl)ethyl]propane-1,3-diol, in free form or in salt form, which process comprises
gxe2x80x2) reducing a compound of formula (20) as defined above under conditions to obtain a compound of formula (21xe2x80x2) 
wherein R and R3 are as defined above; and
y) hydrogenating the resulting compound of formula (21xe2x80x2) to obtain a compound of formula (21xe2x80x3) 
wherein R and R3 are as defined above; and
z) treating the resulting compound of formula (21xe2x80x3) with a basic compound.
Process step (gxe2x80x2) is a reduction carried out in the same manner as in step (g). Suitable reducing agents may be e.g. as disclosed above for step (g). Steps (y) and (z) may be carried out as disclosed above for steps (j) and (N).
As an alternative to above step (y),
ixe2x80x2) a compound of formula (21xe2x80x2) as defined above may be reacted with a basic compound, e.g. an alkali metal hydroxide, to obtain a compound of formula (22) as defined above, which compound of formula (22) is then further treated as disclosed above for step (j).
Suitable alkali metal hydroxide may be e.g. LiOH.
Compound of formula (20), used as starting product in the preparation of a 2-amino-2-[2-(4-C2-20alkylphenyl)ethyl]propane-1,3-diol, is novel and also forms part of the present invention, as well as its preparation. Compound of formula (20) may be obtained by a process comprising
a) reacting a compound of formula (16) 
wherein R is as defined above, with 2-bromoacetyl chloride to obtain a compound of formula (18) 
wherein R is as defined above; and
d) reacting the resulting compound of formula (18) with a compound of formula (2) 
wherein R1 to R3 are as defined above.
Process step (a) may be performed in accordance with known bromoacetylation methods, e.g. in the presence of AlCl3. Process step (d) may conveniently be effected in the presence of sodium ethylate, in an anhydrous solvent such as anhydrous ethanol, and under an inert atmosphere, e.g. nitrogen, e.g. as disclosed in Example 13. Compound of formula (18) used in above step (d) may also be prepared by reacting a compound of formula (16) as defined above, with acetyl chloride to obtain a compound of formula (18xe2x80x2) 
wherein R is as defined above, which compound of formula (18xe2x80x2) is then brominated.
In a further or alternative embodiment, the invention further provides a process for preparing a 2-amino-2-[2-(4-C2-20alkylphenyl)ethyl]propane-1,3-diol, in free form or in salt form, which process comprises
H) reacting a compound of formula (7) 
wherein R is as defined above, with a compound of formula (2) as defined above, to obtain a compound of formula (8) as defined above; and
further submitting the resulting compound of formula (8) first to step (K) and then to step (N) as disclosed above.
Process step (H) may preferably be effected in the presence of sodium ethylate, e.g. as disclosed for step (d) above.
Compound of formula (7) used in process step (H) may be prepared by
c) iodinating a compound of formula (19) 
wherein R is as defined above; or
I) reducing a compound of formula (7xe2x80x2) 
wherein Rxe2x80x2 is as defined above.
Process step (c) may conveniently be performed by reaction with an iodinating agent, e.g. an alkali metal iodide such as Nal or Kl. Process step (I) may be carried out under acidic conditions, e.g. trifluoroacetic acid. Suitable reducing agents include e.g. triethylsilane.
Compound of formula (19), used as starting product in the preparation of 2-amino-2-[2-(4-C2-20alkylphenyl)ethyl]propane-1,3-diol, is novel and also forms part of the present invention as well as its preparation. Compound of formula (19) may be obtained by
C) hydrogenating a compound of formula (10) 
wherein Rxe2x80x2 is as defined above, to obtain a compound of formula (5) 
wherein R is as defined above; and
Cxe2x80x2) brominating the resulting compound of formula (5).
Process step (C) may be performed as disclosed e.g. for (j). Process step (Cxe2x80x2) may be carried out in accordance with methods known in the art, e.g. using a brominating agent, e.g. HBr, in the presence of a phase transfer-catalyst, e.g. an ammonium salt such as tricaprylmethylammonium halogenide, and further purification using e.g. aluminium oxide.
Compound of formula (19) may also be prepared by
b) reducing a compound of formula (18) as defined above.
Process step (b) may be carried out as disclosed for step (I) above.
Compound of formula (19) is useful to prepare the intermediary compound of formula (8) used in process step (K)
e) directly by reaction with a compound of formula (2) as defined above, preferably in the presence of a base, e.g. an alkali metal hydride such as NaH, or an alkali metal alkoxide, e.g. C2H5 ONa or t.-C4H9OK.
Process step e) may be carried out in accordance with known methods or e.g. as disclosed in Example 20.
According to the invention, Compound A is preferably prepared
either starting from a compound of formula (19) and following above disclosed route: step (e)step (K)step (N);
or starting from a compound of formula (7) and following above disclosed route: step (H)step (K)step (N),
or starting from a compound of formula (20) or (20xe2x80x2) and following above disclosed route: step (f)step (K)step (N).
The present invention also comprises each of the following steps disclosed above, respectively: step (b), step (c), step (Cxe2x80x2), step (e), step (d), step (gxe2x80x2), step (g), step (x), step (f).
Examples of salts include salts with inorganic acids, such as hydrochloride, hydrobromide, and sulfate, salts with organic acids, such as acetate, lactate, succinate or tartarate, fumarate, maleate, benzoate, citrate, malate, methanesulfonate and benzenesulfonate salts. Preferred salt is the hydrochloride salt. 2-amino-2-[2-(4C2-20alkylphenyl)ethyl]propane-1,3-diols, preferably Compound A, may be converted into the hydrochloride salt form in accordance with known methods, e.g. by addition of HCl to the last reaction step such as in step (j), or prior to recrystallization such as in step (N).
2-Amino-2-[2-(4-C2-20alkylphenyl)ethyl]propane-1,3-diols and/or the intermediate compounds may be purified and/or separated by a conventional manner such as recrystallization, column chromatography, distillation, centrifugal separation, washing or drying.
The present Examples are illustrative of the invention.